Bioactive glasses are well known surgical materials that have been used as bone graft materials for over 24 years. The original 45S5 bioactive glass composition was discovered by Hench and has the following composition: 45% SiO2, 24.5% Na2O, 24.5% CaO and 6% P2O5 [Hench J. Biomed. Mater. Res. Symp. 117-141 (1971)]. As a bone graft material, bioactive glasses have the unique property of forming a hydroxy-carbano-apatite (HCA) layer on the glass surface when implanted in vivo. The formation of this layer is linked to the glass dissolution, subsequent release of calcium (Ca) and phosphorus (P) ions, and the formation of a Ca—P rich layer on the glass surface. The layer eventually crystallizes into hydroxy-carbano-apatite and results in an interfacial bond between the bioactive glass and the bone which improves bone healing around the bioactive glass particles.
Following the Hench's original discovery of the 45S5 formula, additional compositions were evaluated but it was found that only a narrow range of the CaO—SiO2—Na2O ratio was bioactive with the 45S5 composition providing the best results. Hench et al Life Chem Rep 13: 187 (1996).
Work was also conducted on determining an optimal particle size. Initially, this was focused on improving intraoperative handling of the wet glass during surgery. Low et al. (U.S. Pat. No. 4,851,046) examined the effect of 45S5 bioactive glass particle size on the intraoperative cohesiveness and manipulation of the glass. Testing showed that a broad 90-710 μm particle size had the best intraoperative handling and in vivo bone formation in a primate periodontal defect.
Schepers and Ducheyne (U.S. Pat. No. 5,204,106) also examined the effects of 45S5 bioactive glass particle size. This was done to control the disintegration and dissolution rate of the bioactive glass particles. It was shown that the implantation of various particle sizes in the canine jaw bone resulted in different biological responses to the glass. The results showed that the 280-425 μm size range provided the best bone formation response at this skeletal site.
Although the results from the prior jaw bone study found sub-optimal responses for smaller particles, this was attributed to the higher fluid flow and vascularity in the jaw. This led to faster resorption of the glass before sufficient bone growth could occur. The appendicular skeleton, however, has lower vascularity and minimal fluid flow as compared to the jaw. Following their original dental study, Schepers and Ducheyne (U.S. Pat. No. 5,658,332) found that smaller particles (200-300 μm) of bioactive glass implanted in the appendicular skeleton did not resorb at the fast rate seen in the jaw. They found that the smaller size range increased the bone formation rate by providing a nuclei for bone tissue formation. Testing conducted in a rabbit iliac crest defect showed that the 200-300 μm particle size supported bone growth on the surface of the particles (osteoconduction) and within the central area of the particles (excavation). Additionally, in vivo testing of various glass compositions showed that the 45S5 glass had the best bone formation.
Further work by Yang (U.S. Pat. No. 6,228,386) addressed the cost issue related to manufacturing narrow ranges of bioactive glass. Yang's work expanded Schepers and Ducheyne's 200-300 μm to 200-400 μm in order to reduce the manufacturing cost of the bioactive glass particles. This broader size range was tested in an in vivo rabbit iliac crest model and was compared against Schepers and Ducheyne's 200-300 μm range and the original 90-710 μm range disclosed by Low. Although the results were semi-quantitative and were based on 2 animals per group, the data did show that the slightly broader 200-400 μm had the best performance.
The prior art showed that particle size had effects on particulate intra-operative handling, glass dissolution, function as a bone nucleation site, and manufacturing costs. Following this initial work, it was discovered that a new characteristic of the glass was the main contributors to bioactive glass bone healing. In a study by Oonishi, 45S5 bioactive glass was compared directly against a widely used bone graft material (hydroxyapatite) in an in vivo rabbit femur model [Oonishi et al. Clin. Orthop. Rel. Res. 334:316-325 (1997)]. The results showed that the bioactive glass resulted in faster and more robust bone formation than hydroxyapatite. Oonishi hypothesized that the increased bone formation with 45S5 glass was attributed to the release of silica, calcium, and phosphorus ions which stimulated the colonization and proliferation of stem cells on the surface of the glass. This finding was later confirmed by several studies which showed that the ions released from bioactive glass increased bone formation through enhanced cellular differentiation, proliferation, and protein expression [Xynos et al. Biochem Biophys Res Commun 276: 461-465 (2000); Bosetti et al Biomaterials 26: 3873-3879 (2005); Jell et al. J. Mater. Sci: Mater. Med. 17:997-1002 (2006)].
Although the original bioactive glass optimization data evaluated the size of the glass particle, all of this work was based on using irregular glass particles and did not take into account the recent data showing that ion release has a significant impact on the ability of bioactive glass to promote bone healing. The irregularly-shaped particles of the prior art were sieved to specific size ranges and had a highly irregular and random shape with rough, jagged edges. In addition, the isolation of specific size ranges is not completely accurate due to oblong, “rice grain” shaped particles that may or may not pass through the sieve during the separation process.
The prior art has also shown that bioactive glass that is too small can quickly dissolve and lead to a burst release of ions to the site that could have a detrimental effect on bone healing (U.S. Pat. No. 5,658,332). Conversely, particles that are too large may release the ions too slowly and the bioactive glass would not benefit from the short-term ionic stimulation of local cells. Further, the teachings of the prior art indicate that it is essential to utilize irregular-shaped, rough-edged particles with microcracks in order to achieve a beneficial bone healing response.
Further optimization of bioactive glass particle shape and size to produce new materials is needed to further improve the bone-healing response.